tbuckley/cabot-search huggingface dataset:
Self-amplifying RNA vaccine protects mice against lethal Ebola virus infection
Authors: Verena Krähling, Stephanie Erbar, Alexandra Kupke, Sara S. Nogueira, Kerstin C. Walzer, Hendrik Berger, Erik Dietzel, Sandro Halwe, Cornelius Rohde, Lucie Sauerhering, Letícia Aragão-Santiago, Jorge Moreno Herrero, Sonja Witzel, Heinrich Haas, Stephan Becker, Ugur Sahin
Journal: Molecular Therapy (2022)

Emerging and re-emerging viruses, such as Zaire Ebola virus (EBOV), pose a global threat and require immediate countermeasures, including the rapid development of effective vaccines that are easy to manufacture. Synthetic self-amplifying RNAs (saRNAs) attend to these needs, being safe and strong immune stimulators that can be inexpensively produced in large quantities, using cell-free systems and good manufacturing practice. Here, the first goal was to develop and optimize an anti-EBOV saRNA-based vaccine in terms of its antigen composition and route of administration. Vaccinating mice with saRNAs expressing the EBOV glycoprotein (GP) alone or in combination with the nucleoprotein (NP) elicited antigen-specific immune responses. GP-specific antibodies showed neutralizing activity against EBOV. Strong CD4
An expanded arsenal of immune systems that protect bacteria from phages
Authors: Adi Millman, Sarah Melamed, Azita Leavitt, Shany Doron, Aude Bernheim, Jens Hör, Jeremy Garb, Nathalie Bechon, Alexander Brandis, Anna Lopatina, Gal Ofir, Dina Hochhauser, Avigail Stokar-Avihail, Nitzan Tal, Saar Sharir, Maya Voichek, Zohar Erez, Jose Lorenzo M. Ferrer, Daniel Dar, Assaf Kacen, Gil Amitai, Rotem Sorek
Journal: Cell Host & Microbe (2022)
Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity
Authors: Ines Marin, Olga Boix, Andrea Garcia-Garijo, Isabelle Sirois, Adrià Caballe, Eduardo Zarzuela, Irene Ruano, Camille Stephan-Otto Attolini, Neus Prats, José A López-Domínguez, Marta Kovatcheva, Elena Garralda, Javier Muñoz, Etienne Caron, María Abad, Alena Gros, Federico Pietrocola, Manuel Serrano
Journal: Cancer Discovery (2022)

Abstract Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses. Significance: Our study shows that senescent cells are endowed with a high immunogenic potential—superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses. See related article by Chen et al., p. 432. This article is highlighted in the In This Issue feature, p. 247
Tuning neurodegeneration-linked gene expression, one (edited) base at a time
Authors: Rosa Selenia Guerra-Resendez, Daniel Brenner, Isaac B. Hilton
Journal: Molecular Therapy (2022)

Dysregulated gene expression is a frequent hallmark of neurodegenerative diseases. Thus, strategies that enable precise and targeted tuning of endogenous gene expression represent an attractive approach for neurodegenerative-focused gene therapies. In this issue, Lim et al. 1 Lim C.K.W. McCallister T.X. Saporito-Magriña C. McPheron G.D. Krishnan R. Zeballos C.M.A. Powell J.E. Clark L.V. Perez-Pinera P. Gaj T. CRISPR base editing of cis-regulatory elements enables the perturbation of neurodegeneration-linked genes.. Mol Ther. 2022; 30: 3619-3631 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar employ CRISPR base editors to modify cis-regulatory sequences that govern the expression of two key genes involved in neurodegenerative diseases - the HTT gene for Huntington’s disease (HD), and the APP gene for Alzheimer’s disease (AD). By performing a focused, tiled CRISPR interference (CRISPRi) screen, Lim et al. identify functional elements embedded within the HTT promoter, most importantly an NF-κB binding site, that tune HTT expression levels. The authors build upon these findings and show that using cytosine base editors (CBEs) at this pivotal NF-κB binding site can induce marked reduction in HTT mRNA levels and consequently, nearly a two-fold decrease in HTT protein levels in HEK293T cells. Further, by targeting the CBE to the HTT promoter in vivo using AAV1, the authors were able to reduce HTT mRNA levels by ∼50% compared to control animals in the R6/2 mouse model of HD. Finally, Lim et al. showed that combinations of different CBEs could be used to modulate neurodegenerative-associated gene expression in a synergistic manner, resulting in even greater repression. Collectively, this work highlights the rising promise and utility of base editing technologies for therapeutic intervention, particularly at endogenous non-coding regulatory elements.
Mapping neurotransmitter systems to the structural and functional organization of the human neocortex
Authors: Justine Y. Hansen, Golia Shafiei, Ross D. Markello, Kelly Smart, Sylvia M. L. Cox, Martin Nørgaard, Vincent Beliveau, Yanjun Wu, Jean-Dominique Gallezot, Étienne Aumont, Stijn Servaes, Stephanie G. Scala, Jonathan M. DuBois, Gabriel Wainstein, Gleb Bezgin, Thomas Funck, Taylor W. Schmitz, R. Nathan Spreng, Marian Galovic, Matthias J. Koepp, John S. Duncan, Jonathan P. Coles, Tim D. Fryer, Franklin I. Aigbirhio, Colm J. McGinnity, Alexander Hammers, Jean-Paul Soucy, Sylvain Baillet, Synthia Guimond, Jarmo Hietala, Marc-André Bedard, Marco Leyton, Eliane Kobayashi, Pedro Rosa-Neto, Melanie Ganz, Gitte M. Knudsen, Nicola Palomero-Gallagher, James M. Shine, Richard E. Carson, Lauri Tuominen, Alain Dagher, Bratislav Misic
Journal: Nature Neuroscience (2022)

Abstract Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.
Spironolactone effect on cardiac structure and function of patients with heart failure and preserved ejection fraction: a pooled analysis of three randomized trials
Authors: João Pedro Ferreira, John G. Cleland, Nicolas Girerd, Erwan Bozec, Patrick Rossignol, Pierpaolo Pellicori, Franco Cosmi, Beatrice Mariottoni, Scott D. Solomon, Bertram Pitt, Marc A. Pfeffer, Amil M. Shah, Johannes Petutschnigg, Burkert Pieske, Frank Edelmann, Faiez Zannad
Journal: European Journal of Heart Failure (2022)
A developmental atlas of somatosensory diversification and maturation in the dorsal root ganglia by single-cell mass cytometry
Authors: Austin B. Keeler, Amy L. Van Deusen, Irene C. Gadani, Corey M. Williams, Sarah M. Goggin, Ashley K. Hirt, Shayla A. Vradenburgh, Kristen I. Fread, Emily A. Puleo, Lucy Jin, O. Yipkin Calhan, Christopher D. Deppmann, Eli R. Zunder
Journal: Nature Neuroscience (2022)
Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome
Authors: Daan H.H.M. Viering, Marguerite Hureaux, Kornelia Neveling, Femke Latta, Michael Kwint, Anne Blanchard, Martin Konrad, René J.M. Bindels, Karl-Peter Schlingmann, Rosa Vargas-Poussou, Jeroen H.F. de Baaij
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3 , which encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). A subset of patients with Gitelman syndrome has only one specific pathogenic variant identified. In this study, long-read sequencing identified 46 previously undetected variants in 95 patients with suspected Gitelman syndrome. A midigene splice assay confirmed the pathogenicity of intronic variants. The data show that both intronic and exonic variants were missed previously and that former detection of one SLC12A3 variant predicts identification of an additional variant. The findings advocate long-read sequencing, complemented with a midigene splice assay, for intronic variants, as a second-tier diagnostic test in patients with one pathogenic SLC12A3 variant. Background Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl − cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield. Methods Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants. Results A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C&gt;T variant and intronic candidate variants demonstrated aberrant splicing patterns. Conclusion Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.
Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4
Authors: Yan Mo, Shoufu Duan, Xu Zhang, Xu Hua, Hui Zhou, Hong-Jian Wei, Jun Watanabe, Nicholas McQuillan, Zhenyi Su, Wei Gu, Cheng-Chia Wu, Christopher R. Vakoc, Rintaro Hashizume, Kenneth Chang, Zhiguo Zhang
Journal: Cancer Discovery (2022)

Patients with diffuse midline gliomas that are H3K27 altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration, and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 colocalizes with SOX10 at gene regulatory elements to control the expression of genes involved in cell growth and the extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG. DMG is a deadly pediatric glioma currently without effective treatments. We discovered that the chromatin remodeler SMARCA4 is essential for the proliferation of DMG with H3K27M mutation in vitro and in vivo, identifying a potentially novel therapeutic approach to this disease. See related commentary by Beytagh and Weiss, p. 2730. See related article by Panditharatna et al., p. 2880. This article is highlighted in the In This Issue feature, p. 2711.
Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
Authors: Young Mi Oh, Seong Won Lee, Woo Kyung Kim, Shawei Chen, Victoria A. Church, Kitra Cates, Tiandao Li, Bo Zhang, Roland E. Dolle, Sonika Dahiya, Stephen C. Pak, Gary A. Silverman, David H. Perlmutter, Andrew S. Yoo
Journal: Nature Neuroscience (2022)
Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus‐associated oropharyngeal cancer
Authors: Jung Julie Kang, Yao Yu, Linda Chen, Kaveh Zakeri, Daphna Yael Gelblum, Sean Matthew McBride, Nadeem Riaz, C. Jillian Tsai, Anuja Kriplani, Tony K. W. Hung, James V. Fetten, Lara A. Dunn, Alan L. Ho, Jay O. Boyle, Ian S. Ganly, Bhuvanesh Singh, Eric J. Sherman, David G. Pfister, Richard J. Wong, Nancy Y. Lee
Journal: CA A Cancer Journal for Clinicians (2022)

Abstract The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long‐term morbidities with chemoradiation and the favorable prognosis of HPV‐positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head‐and‐neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de‐escalation. National database studies estimate that up to one third of patients receive nonstandard de‐escalated treatments, which have subspecialty‐specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV‐positive OPC de‐escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de‐escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy‐based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de‐escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real‐time surveillance.
Incomplete preferences and rational framing effects
Authors: Shlomi Sher, Craig R M McKenzie
Journal: Behavioral and Brain Sciences (2022)

Abstract The normative principle of description invariance presupposes that rational preferences must be complete. The completeness axiom is normatively dubious, however, and its rejection opens the door to rational framing effects. In this commentary, we suggest that Bermúdez's insightful challenge to the standard normative view of framing can be clarified and extended by situating it within a broader critique of completeness.
Meta-Analysis of the Test–Retest Repeatability of [18F]-Fluorodeoxyglucose Standardized Uptake Values: Implications for Assessment of Tumor Response
Authors: Lalitha K. Shankar, Erich Huang, Saskia Litiere, Otto S. Hoekstra, Larry Schwartz, Sandra Collette, Ronald Boellaard, Jan Bogaerts, Lesley Seymour, Elisabeth G.E. deVries
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice. Experimental Design: Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test–retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test–retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics. Results: Test–retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes. Conclusions: On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET–based criteria that assess clinically significant changes in tumor response.
Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data
Authors: Ash B. Alpert, Jamie Renee Brewer, Spencer Adams, Lexis Rivers, Sunshine Orta, John R. Blosnich, Susanne Miedlich, Charles Kamen, Don S. Dizon, Richard Pazdur, Julia A. Beaver, Lola Fashoyin-Aje
Journal: Journal of Clinical Oncology (2022)
A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma
Authors: John A. Ligon, R. Taylor Sundby, Mary F. Wedekind, Fernanda I. Arnaldez, Jaydira Del Rivero, Lori Wiener, Ramaprasad Srinivasan, Melissa Spencer, Amanda Carbonell, Haiyan Lei, John Shern, Seth M. Steinberg, William D. Figg, Cody J. Peer, Sara Zimmerman, Josquin Moraly, Xia Xu, Stephen Fox, King Chan, Michael I. Barbato, Thorkell Andresson, Naomi Taylor, Karel Pacak, J. Keith Killian, Eva Dombi, W. Marston Linehan, Markku Miettinen, Richard Piekarz, Lee J. Helman, Paul Meltzer, Brigitte Widemann, John Glod
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer–associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. Patients and Methods: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. Results: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18–57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1–17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. Conclusions: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
Early Effect of the Circular Model of Kidney Allocation in the United States
Authors: Chethan M. Puttarajappa, Sundaram Hariharan, Xingyu Zhang, Amit Tevar, Rajil Mehta, Vikraman Gunabushanam, Puneet Sood, William Hoffman, Sumit Mohan
Journal: Journal of the American Society of Nephrology (2022)

In March 2021, the United States implemented a new kidney allocation system (KAS250) for deceased donor kidney transplantation (DDKT), which eliminated the donation service area-based allocation and replaced it with a system on the basis of distance from donor hospital to transplant center within/outside a radius of 250 nautical miles. The effect of this policy on kidney discards and logistics is unknown.